This is a proposal for an ADAMSHA SDA which focuses on the regulation and interaction of the Hypothalamic-Pituitary-Adrenal (LHPA) axis and the Serotonin (5HT) system in human brain. Dysfunction of the lHPA (or "brain stress") axis and of the 5HT) system are two of the strongest findings in both depression and suicide. It is known from animal studies that they are related in a variety of ways and that molecules from the two systems are co-localized in brain regions such as the limbic system, including the hippocampus and the hypothalamus, as well as in the dorsal and median raphe nucleus. The fundamental goal of this proposal is to study the interactions of the LHPA brain stress axis and the 5HT system in the brains of suicide victims using biochemical and neuroanatomical tools (specific aims 1 & 2). It is also known from animal studies that both chronic stress and very high steroid levels (the final product of the LHPA) axis) may cause neuronal cell loss in the hippocampus. Since the circumstances leading to suicide can be constructed as a chronic stress condition, this project will also evaluate if there are any neuropathological abnormalities in the limbic system of suicide victims (specific aim 3), in particular in the areas rich in 5HT and lHPA related molecules. To achieve our goals, we will use receptor autoradiography, in situ hybridization, quantitative morphometric analysis and immunocytochemistry to quantify: 1. 5HT receptor binding and mRNA levels in the limbic system, hypothalamus and raphe nuclei; 2. glucocorticoid (GR) and mineralocorticoid (MR) receptor mRNA levels in the same regions; 3. corticotropin releasing hormone and arginine vasopressin mRNA levels in the hypothalamus; 4. neuronal loss an/or degeneration in the limbic system. We will compare these parameters between suicide victims and accidental death victims (matched for age, gender and post-mortem time). Using "psychological autopsies" to gather relevant clinical information, we will assess: 1. if changes in these systems are specific for depression, or are found in all suicide victims irrespective of diagnosis and 2. what is the influence of clinical and demographic factors on these biochemical parameters (age, gender, duration of illness, etc.).